A 28-year-old woman with newly diagnosed sputum-positive pulmonary TB is started on standard anti-TB therapy (HRZE for 2 months, then HR for 4 months). She is 8 weeks into treatment and reports new-onset jaundice, dark urine, and right upper quadrant pain. Liver function tests show: ALT 320 U/L, AST 280 U/L, ALP 180 U/L, total bilirubin 4.2 mg/dL. What is the most appropriate next step in management?

Explanation

## Clinical Context The patient presents with clinical and biochemical evidence of acute hepatitis (jaundice, dark urine, RUQ pain, marked transaminitis with hyperbilirubinemia) during anti-TB therapy. The differential diagnosis includes: - **Drug-induced liver injury (DILI)** from anti-TB agents (INH, RIF, PZA most common) - **Acute viral hepatitis** (HAV, HBV, HCV, EBV, CMV) - **Autoimmune hepatitis** - **Other causes** (cholecystitis, biliary obstruction) ## Key Point: **Anti-TB drug-induced hepatotoxicity is a medical emergency. The first step is to STOP all hepatotoxic drugs and investigate the etiology before restarting therapy.** Continuing therapy in the presence of severe hepatitis risks acute liver failure. ## High-Yield: **Diagnostic criteria for anti-TB drug-induced liver injury (WHO/NTEP):** - ALT ≥ 3× upper limit of normal (ULN) + symptoms, OR - ALT ≥ 5× ULN regardless of symptoms This patient meets criteria (ALT 320, symptomatic). Immediate cessation is mandatory. ## Management Algorithm ```mermaid flowchart TD A["Patient on anti-TB therapy<br/>with signs/symptoms of hepatitis"]:::outcome A --> B["Check LFTs:<br/>ALT, AST, ALP, Bili"]:::action B --> C{"ALT ≥ 3× ULN<br/>+ symptoms?"}:::decision C -->|Yes| D["STOP all anti-TB drugs<br/>immediately"]:::urgent C -->|No| E["Continue therapy<br/>Monitor LFTs"]:::action D --> F["Investigate etiology:"]:::action F --> G["• Hepatitis serology<br/>• Imaging (US/CT)<br/>• Exclude other causes"]:::action G --> H{"Drug-induced<br/>or other cause?"}:::decision H -->|Drug-induced| I["Restart TB drugs in order:<br/>1. RIF (safest)<br/>2. INH<br/>3. PZA (most toxic)<br/>Rechallenge protocol"]:::action H -->|Viral/other| J["Treat underlying cause<br/>Restart TB drugs after<br/>LFTs normalize"]:::action ``` ## Rechallenge Protocol (if DILI confirmed) 1. **Restart rifampicin first** (safest; restart at full dose) 2. **After 2–3 days, add isoniazid** (if LFTs stable) 3. **After 2–3 days, add pyrazinamide** (most hepatotoxic; restart last) 4. **Monitor LFTs closely** during rechallenge ## Clinical Pearl: Continuing anti-TB drugs in the presence of symptomatic hepatitis with ALT > 300 U/L is contraindicated and risks fulminant hepatic failure. The temporary interruption allows investigation and safe rechallenge. [cite:NTEP Guidelines 2022, Harrison 21e Ch 158, Robbins 10e Ch 18]